We have entered the cell, the Mansion of our birth, and started the inventory of our acquired wealth.— Albert Claude, Cell Biologist and
Nobel Prize Laureate, 1974

A
very long time ago—about 2.2 billion years before now—an astonishing invasion occurred. Members of one branch of living things, a form of bacteria (α-proteo-bacteria), took up residence in the cells of another domain or branch, those of eukaryotes (pronounced you·carry·oats—organisms whose cells contain complex structures inside their membranes). This occupation was not parasitic but endosymbionic, forming an intracellular partnership, in which eukaryotic cells—arising from an Archaea-like ancestor—‘‘hosted’’ the bacteria (now mitochondria) which together evolved a mutually beneficial relationship. Archaea are a primordial group comprised of single-celled microorganisms. They have no cell nucleus or any other organelles within their cells.

Glorious Evolution

The product of the mutually beneficial partnership, eukaryotic nuclear genomes, are first and foremost retooled archaeal genomes (see Figure 1), that branched from the main stock prior to the invasion of the mitochondria, and the concomitant partnership that derived. After the divergent split, a few α-proteobacterial genes, whose products still function in mitochondria, were transferred to the nucleus of the eukaryotes. We humans are a product of this genomic collusion and glorious evolutionary step forward.

Fig. 1

The Ability to Increase Mitochondria Count

We have written before about mitochondria with some frequency (most recently,
“Enhance Your Cellular Power” in the July 2009 issue) and discussed the role that they play in maintaining youthfulness and fighting the aging process. Even though mitochondria are the focus of a major theory of aging—and thus a principal concern to life extensionists—it wasn’t until a paper was published a few years ago on resveratrol use in mice that attention has turned to more immediate possibilities (see
“Resveratrol Boosts Strength and Endurance in Mice” in the February 2007 issue).

Quercetin can also help to recover the loss of age-related strength.

What if we could really raise the power of our own cell energy managers, as the Lagouge et al. paper indicates resveratrol appears able to do with mice?1 In this celebrated research, resveratrol was found to mediate a decrease in PGC-1α acetylation, thereby causing an increase in PGC-1α activity. This is thought to control mitochondrial biogenesis and function because PGC-1α is a strong arbiter of cellular energy metabolism. When this protein is deacetylated, its biological activity increases, and so do mitochondrial number and function. Analysis of numerous genes involved in energy metabolism and oxidative stress showed large increases in the expression of the genes that code for SIRT1—the sirtuin enzyme which deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity)—and for a protein with the formidable name peroxisome proliferator-activated receptor gamma coactivator-1α (even its formal abbreviation, PPARGC-1α, is so long that it has its own abbreviation, PGC-1α). This tongue-twister is known to be a crucial cofactor in promoting mitochondrial biogenesis . . . and SIRT1 is known to activate PGC-1α . . . and resveratrol is known to activate SIRT1 . . . the dots are connected.

Its ability to enhance the value of exercise on fitness, even without explicit training, may have
important implication for not only athletic and military performance,
but also for the rest of us.

Quercetin Joins Resveratrol for Mitochondrial Biogenesis

Recently we wrote about findings that quercetin looks as if it is also a mitochondrial biogenesis promoter (see
“Quercetin Improves Exercise Tolerance” in the August 2009 issue) and that it can also help to recover the loss of age-related strength. Quercetin is a plant-derived flavonoid, specifically a flavanol, used as a nutritional supplement. It is among the most widespread of all flavonoids, with broad-spectrum bioactive effects, including anti-inflammatory, antipathogenic, and antioxidant activities; immunoregulatory influences; and central nervous system, and muscle mitochondrial biogenesis stimulatory effects.

One of the most pervasive aspects of aging is the loss of strength. So anything that safely increases our ability to stay strong is of major importance. With the study referenced by
“Quercetin Improves Exercise Tolerance,”2 quercetin has entered a new arena of health benefits. Its ability to enhance the value of exercise on fitness, even without explicit training, may have important implication for not only athletic and military performance, but also for the rest of us. These benefits of quercetin may also extend to the prevention and treatment of chronic diseases, thereby extending the quality and perhaps even the quantity of our lives.

Quercetin Effects Enhanced by Other Nutrients

In another recent paper, evidence is presented that quercetin may be helped by other nutrients to enhance the value of exercise for improved fitness.3 Thirty-nine trained cyclists were given 1000 mg of quercetin (Q) along with (or without) 120 mg of epigallocatechin 3-gallate (EGCG), 400 mg of isoquercetin, and 400 mg of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid DHA (Q-EGCG). Then, the effects of the supplements were measured on exercise performance, muscle mitochondrial biogenesis, and changes in measures of immunity and inflammation before and after 3 continuous days of heavy exertion.

The cyclists were randomized to placebo (P), Q, or Q-EGCG after which they ingested the supplements in a double-blinded fashion for 2 weeks before, during, and 1 week after the 3-day heavy exercise period. The exercise entailed cycling for 3 hours per day at approximately 57% maximal workload. Blood, saliva, and muscle biopsy samples were collected before and after 2 week of supplementation and immediately after the exercise bout on the third day. Blood and saliva samples were also collected 14 hours after exercise.

False Assumptions about Quercetin’s Half-Life

In two prior studies with human athletes,4–7 3 weeks of 1000-mg/day quercetin supplementation failed to counter exercise-induced alterations in immunity, inflammation, and oxidative stress. One potential weakness of these studies was the ingestion of the quercetin supplements 10–24 hours before completion of the exercise, a period that may have been too long given the short half-life of quercetin. Because there is increasing support for coingestion of quercetin with other flavonoids and food components, to counter its short-half life, and thus improve and extend quercetin’s bioavailability and bioactive effects, the current cyclist study was different in these regards.

Altogether, these data suggest that quercetin may have a larger effect on untrained muscle, which has a
lower mitochondrial density,
than in trained muscle.

Thus, at the end of the cyclist study, there was a significant increase in plasma quercetin for Q and Q-EGCG and granulocyte oxidative burst activity (GOBA), a measure of a white blood cell count, in Q-EGCG. Significantly, immediately after the third exercise bout, decreases for C-reactive protein (CRP)—an important measure of inflammation—and plasma interleukin 6 and interleukin 10 were measured in Q-EGCG compared with P. Granulocyte colony-stimulating factor (G-CSF) and CRP also were reduced in Q-EGCG 14 hours after exercise.

No group differences were measured in muscle messenger RNA expression for PGC-1α, citrate synthase, or cytochrome c. The researchers found that 2-week supplementation with Q-EGCG was effective in augmenting GOBA and in countering inflammation after 3 days of heavy exertion in trained cyclists.

Less Soreness When Taken Sooner

The Q-EGCG supplement was formulated to improve the bioavailability and bioactive effects of quercetin, and the research design was changed to emphasize ingestion of half the daily dose 1 hour before heavy exertion. The quercetin supplement (without added components) was related to some effects that the researchers previously did not find, including a decrease in total blood leukocytes and G-CSF the morning after 3 days of heavy exertion, a reduction in plasma interleukin-10 after exercise, and a lowered delayed onset of muscle soreness 3 days afterward.

Widespread Antinflammatory Effects with Coingestion

The Q-EGCG supplement produced more widespread effects on inflammation (in particular, reduced CRP and interleukin-6). These effects appear to have been related to the coingestion of quercetin with isoquercetin, EGCG, EPA, and DHA. The morning after the intensified exercise, plasma quercetin levels in Q-EGCG were elevated 98% greater than P and 54% greater than that in Q, thus supporting the concept of a more prolonged quercetin effect from ingestion of the quercetin cocktail supplement. However, no group differences were measured for the cycling time trial performance (after a substantial exercise preload) or mRNA expression for three genes related to muscle mitochondrial biogenesis.

Larger Effect on Untrained Muscle

In another study of 11 elite male cyclists, researchers reported a 1.7% 30-km time trial performance enhancement greater than placebo after 6 weeks of quercetin supplementation.8 Using a randomized, double-blinded, crossover design, this study involved an exercise regimen employing a mountainous terrain format without an exercise preload. Another study (previously referenced2), using sedentary mice, showed that 7 days of quercetin feeding (both 12.5 and 25 mg/kg) increased cytochrome c concentration and citrate synthase activity in soleus muscle by 20%–30%.2 Quercetin feedings also increased treadmill run time to fatigue by approximately 30%, with both quercetin doses equally effective. Altogether, these data suggest that quercetin may have a larger effect on untrained muscle, which has a lower mitochondrial density, than in trained muscle.

Furthermore, the data from available studies suggest that if a muscle mitochondrial biogenesis and performance effect exists in endurance athletes, quercetin supplementation may need to be 6 weeks or longer, and the magnitude may be well below what could be measured in untrained subjects. Summing up, a quercetin supplement combined with EGCG, isoquercetin, and N3-PUFA was more effective than quercetin alone in partially countering exercise-induced inflammation, but without effects on cycling time trial performance or muscle mitochondrial biogenesis compared with placebo.

If a muscle mitochondrial biogenesis and performance effect exists in endurance athletes,
quercetin supplementation
may need to be 6 weeks or longer.

Quercetin Better When Coingested

These data add to the growing literature support for the concept that quercetin’s anti-inflammatory effects are amplified when coingested with other flavonoids, food components, and micronutrients. Additional research is needed to determine whether the proportions and amounts used in this study (i.e., 1000 mg of quercetin, 400 mg of isoquercetin, 120 mg of EGCG, 400 mg of N3-PUFA) are optimal and whether additional food components might add to the effects measured in this study.* The duration of supplementation used in this study (2 weeks before intensified exercise) was based in part on quercetin pharmacokinetic data and findings from animal studies, but Q-EGCG’s countermeasure effects may benefit from a more prolonged supplementation period. Cycling induces less muscle damage, inflammation, and oxidative stress than running, and findings reported in this study on cyclists may differ in magnitude from those measured in competitive marathon runners.

* If you’re wondering, cyclist Lance Armstrong’s FRS® ready-to-drink soda contains 325 mg quercetin and 65 mg catechins (EGCG is the primary type of catechin found in the drink) in an 11.5 fl oz can. But there are no N3-PUFAs and no isoquercetin in FRS.

The Lesson Learned

In another study just published, by Nieman et al, researchers determined the influence of 2-weeks quercetin at 1000 mg/day compared to placebo supplementation on exercise performance and skeletal muscle mitochondrial biogenesis in 26 young, untrained, approximately 20-year old adults.9 Human subjects may require a higher quercetin dose to more consistently induce mitochondrial biogenesis.

Using a randomized, crossover design with a 2-week washout period, subjects provided blood and muscle biopsy samples pre- and post-supplementation periods, and were given 12-minute time trials on 15% graded treadmills following 60-min moderate exercise pre-loads at 60% VO2max.* The researchers found that the plasma quercetin levels of their subjects rose significantly in the group taking quercetin during the 2-week supplementation period. During the 12-minute trial, the net change in distance achieved was significantly greater during quercetin use compared to placebo. Skeletal muscle mRNA expression also tended to increase for quercetin as did SIRT1, PGC-1α, cytochrome c oxidase, and citrate synthase. Muscle mitochondrial DNA increased significantly for quercetin compared to placebo.

* VO2max (also maximal oxygen consumption, maximal oxygen uptake or aerobic capacity) is the maximum capacity of an individual’s body to transport and utilize oxygen during incremental exercise. It reflects the physical fitness of the individual and is considered the best indicator of cardiorespiratory endurance.

In summary, 1000 mg/d quercetin for two weeks by untrained males was associated with a small but significant improvement in 12-minute treadmill time trial performance, and modest but insignificant increases in the relative copy number of mtDNA and mRNA levels of four genes related to mitochondrial biogenesis. For the biggest advances, it may be better to be “untrained” than elite. However, the elite may be happier with much less than an ordinary person. Vive la untrained! You should also recall that there are other important reasons to take quercetin, aside from enhancing muscle (see
“Defending Yourself Against Virus Infections” in the July 2009 issue).